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Categories : Cardiovascular DiseaseTags : 1 Comment

Why Heart Attacks in the Morning Have Worse Outcomes

On By ModernMedia
Human heart. Credit: Scientific Animations CC4.0

It has long been known that heart attacks occurring in the morning are typically more serious than those that happen at night. While daily variations in stress hormone levels and blood pressure affect cardiac health, these are only part of the picture. There is also the diurnal variation in immune response involved: neutrophils, the body’s ‘first responders’, cause more inflammatory damage in the morning, causing havoc even as they neutralise pathogens.

“They’re the first sentinel, but they come fully loaded,” said Douglas Mann, MD, professor at Washington University School of Medicine in St Louis. “They’re shooting at everything and dumping a lot of toxic granules on the environment. They are indiscriminate in terms of their ability to destroy, and they take out healthy cells in the process.”

But exactly why they are more damaging at night has been a mystery. Now, researchers have found the reason behind this diurnal difference in destructiveness, and also how to tweak the ‘internal clocks’ of these white blood cells so that they cause less damage during sterile inflammation while still protecting against pathogens. Their findings are reported in the Journal of Exploratory Medicine, and are summarised in JAMA news.

Finding the pattern

The researchers, from Spain and Yale University, discovered that the timing of heart attacks significantly affects their severity due to a ‘neutrophil clock’ controlled by circadian rhythms. Neutrophils are more active during the day (activated by the Bmal1 protein) and less active at night (inhibited by the CXCR4 receptor).

Analysing more than 2000 patients with ST-segment elevation myocardial infarction, the researchers found that those who had an MI in the morning suffered worse cardiac damage than those who had them at night. Mouse experiments confirmed this pattern and showed that genetically disabling the Bmal1 protein reduced daytime neutrophil activity, protecting against severe cardiac injury.

This suggests a treatment strategy of tricking neutrophils into remaining in their nighttime inactive state, allowing doctors to reduce inflammation and lessen heart attack damage during daytime hours without compromising the immune system’s ability to fight infections.

Reducing cardiac damage without compromising the immune system

Mice engineered to have high levels of CXCR4 were given a drug compound, ATI2341, which bound to CXCR4 receptors. When heart attacks were induced, the mice showed reduced tissue damage. To test the neutrophils’ pathogen-fighting ability, they were also infected with Staphylococcus aureus or Candida albicans, but the mice were able to overcome the infection – the treated mice even tolerated the Candida infection better than the controls.

Mann explained why controlling the neutrophils was a better option. “Prior trials have tried to neutralise neutrophils or reduce neutrophil numbers entirely,” Mann noted. “But when you get rid of neutrophils, you’re also handcuffing the immune system. Before, it was considered an inevitability that neutrophils killing off infection also meant damaging a lot of tissue.”

The crucial question is of course whether this research in mice can translate to humans.

Luigi Adamo, MD, PhD, director of cardiac immunology at Johns Hopkins University who was not involved in the study, said that the study, one of the first use immune circadian rhythms to modulate inflammation, “offers new insight into neutrophils and a new way to look at this cardiac damage that might even apply to other types of sterile inflammation.”

Adamo struck a note of caution: the extremely low success rate in animal-to-human translation in cardioimmunology. “Immune cells are not always the same when you go from mice to humans,” he said.

Treatment implementation is a major obstacle

Even if this neutrophil clock alteration could be applied to humans, it would be difficult to administer since heart attacks strike without warning.

“If everyone took one of these drugs in the morning when they woke up, maybe it would make heart attacks less severe, but ‘preventive’ means you’re giving it chronically, and I don’t know what would happen with long-term stimulation of that receptor and other cell types,” Mann said. “Their data support the acute application, but in the long term, that’s a whole different story.”

As systemic treatment, the off-target effects of ATI2341 would need to be explored. He also struggled to envision a potential therapeutic solution.

“Today, when you have a heart attack, in most places with hospitals and well-developed health care systems, the patient gets an angioplasty,” Mann said. “The only time this drug could be given would be at the time of reperfusion, when you’re blowing up the balloon and opening up the clot.” Typically, ideal reperfusion timing is within two hours – but neutrophils probably do their damage within a matter of 30 minutes, Mann explained. “It’s a race against time, and I’m curious if [the researchers] can demonstrate that.”

Source: JAMA

Categories : General Interest Medical IndustryTags :

Discovery Abandons R170 Million Clawback over Medicines Reimbursement Glitch

On By ModernMedia
Photo by Scott Graham on Unsplash

Discovery Health has recently abandoned its efforts to reclaim roughly R170 million from 16 507 members following a widespread administrative error in processing medical claims. This happened after the successful intervention of the advocacy group MediCheck, which argued that the affected members were being unfairly penalised for a technical glitch which they had nothing to do with.

The glitch, which happened last year, resulted in over-reimbursement of certain medicine costs that occurred throughout 2025. Several specific technical and procedural issues were involved which caused the problem to grow undetected for nearly a year, as detailed by Moonstone.

The main error was that certain claims were incorrectly reimbursed at 100% of the Discovery Health Rate, regardless of the specific benefit limits that should have applied to those categories, when they should have been reimbursed at a lower rate.

Because these claims were incorrectly reimbursed at higher rates, they were inaccurately accumulated towards members’ benefit thresholds. This caused members who had Above-Threshold Benefit (ATB) as part of their plan to reach it prematurely. Upon reaching the ATB, subsequent medical claims were funded by the scheme. Normally, these claims would have been covered by the members’ medical savings accounts or out-of-pocket contributions.

Delayed detection allowed the problem to grow. The error was particularly difficult to identify because it was a “second-order impact”. The systemic failure only became apparent late in the year when members began reaching the ATB and the financial discrepancies were finally flagged.

This snowballing error eventually affected some 16 507 members on specific Executive, Comprehensive, and Priority plans. While Discovery Health initially sought to recover these funds, ranging from thousands of rand to as much as R80 000 per member, the Council for Medical Schemes stepped in to exert pressure amid widespread media coverage of the situation. Discovery gave in and committed to refunding any recovered funds and absorbing the total financial loss itself – estimated between R130 million and R170 million.

Categories : Ethics and Law Mental HealthTags :

Untangling the Argument Around Prenatal Paracetamol and Autism

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On Monday 22 September, US President Donald Trump made a widely-publicised announcement that paracetamol (acetaminophen/Tylenol) during pregnancy was confirmed as causing autism spectrum disorder (ASD). The claim – backed by a single, rather dodgy study – brings to a head long-standing concerns about the apparent, well-documented increase in ASD rates. QuickNews dives into the controversy to find out if there is any validity to the claims.

President Trump said, “With Tylenol, don’t take it. Don’t take it. And if you can’t live, if your fever is so bad, you have to take one because there’s no alternative to that, sadly,” adding that other medicines such as aspirin were also “proven bad”.

The announcement had been expected for some time and doctors, scientists and medical organisations were quick to respond. The president of the American College of Obstetricians and Gynecologists stated that the paracetamol–ASD claim “is not backed by the full body of scientific evidence and dangerously simplifies the many and complex causes of neurologic challenges in children”.

At the very least, such an announcement will causing pregnant women to second-guess their taking one of the few over-the-counter pain medications widely regarded as safe during pregnancy. In 2017, the X account for Tylenol stated “We actually don’t recommend using any of our products while pregnant.” But a major pharmaceutical manufacturer would want to protect itself from liability as broadly as possible. The politically-charged nature of the announcement has also seen pregnant women making TikTok videos of themselves apparently taking paracetamol (often with no reason to).

It is generally accepted that ASD is caused by a combination of genetics and environmental factors. About 1000 genes are believed to be related to ASD. And there is a very long list of possible risk factors, with an uncertain risk contribution: “Non-genetic factors mediating ASD risk could include parental age, maternal nutritional and metabolic status, infection during pregnancy, prenatal stress, and exposure to certain toxins, heavy metals, or drugs.”

Study validity questioned

To date, paracetamol during pregnancy had generally been linked by a number of poorly powered studies to a wide variety of outcomes: in addition to ASD, asthma, lower performance intelligence quotient (IQ), shorter male infant anogenital distance (predicting poor male reproductive potential), neurodevelopmental problems (gross motor development, communication), attention-deficit/hyperactivity disorder, poorer attention and executive function, and behavioural problems in childhood. A study of nearly 2.5 million children, the largest and most comprehensive do date, found a slight link for paracetamol exposure and autism – which vanished when controlled for sibling exposure (representing shared environment).

Before President Trump’s announcement, news releases on a review making the link were published some weeks before – QuickNews even covered it. The review, published in Environmental Health, selected certain related studies using the ‘Navigation Guide’ methodology – a non-quantitative methodology for the narrow use of inferring health impacts from environmental toxins, but was nevertheless used for pharmaco-epidemiology and teratology. According to Nathan A. Schacthman, legal counsel for scientific matters, the study has serious conflicts of interest: for example, last author Andrea A. Baccarelli is an environmental epidemiologist who has been involved with a lawsuit against manufacturers and sellers of paracetamol. In that lawsuit, his claims were thrown out on the basis of not having sufficient validity, including cherry-picked data and over-generalisation to distinct disorders (such as grouping attention-deficit hyperactivity disorder [ADHD] and other neurodevelopmental disorders). In addition, the study also made misleading claimed about being funded by the National Institutes for Health (NIH). Finally, although this is not mentioned by Schacthman, Robert F. Kennedy Jr. is also an environmental lawyer.

What’s this about a ‘cure’ for autism?

The bombshell announcement by President Trump came with an another bombshell announcement that there was ‘cure’ for autism. The cure is allegedly leucovorin – which sounds very impressive to the non-medical public. But leucovorin is merely folinic acid, which is a vitamer of plain old folic acid – aka vitamin B9. Folinic acid is on the World Health Organization’s essential medicines list. On the same Monday, the US Food and Drug Administration approved it for the treatment of ASD in children – bypassing the normal review process.

Can a simple medication – or rather, supplement – really ‘cure’ ASD, an extremely complex neurological disorder? The NIH funds about $300 million in ASD research annually, nearly double the amount in 2011. If anything, this has echoes of President Trump’s touting of hydroxychloroquine as a now-discredited cure for COVID in the height of the pandemic. It might indeed be beneficial if a patient had a bout of malaria and COVID at the same time, but was rapidly discredited.

The largest controlled study for the use of folinic acid supplementation plus usual care found only a modest ~1 point increase in the Childhood Autism Rating Scale (CARS) compared to usual care plus placebo.

There are also concerns about potential conflicts of interest. One of the manufacturers of folinic acid, iHerb, had the celebrity heart doctor Mehmet Oz as an investor, and is now the administrator for the Centers for Medicare & Medicaid Services (CMS), served until recently. CMS has however denied that Dr Oz will receive any financial reward from this.

But why are autism rates on the rise?

There are a few good explanations about why the rate of autism diagnoses is increasing, which do not depend on the addition of some new environmental variable. The first and most obvious is that there is increased awareness of this, and more referrals for assessment. A second reason is that the guidelines for diagnosis have become a lot less stringent. The definition of autism diagnoses, unlike schizophrenia, has drifted over time, with more “normal” people being likely to be diagnosed. The DSM-III of 1980 had more stringent criteria, for example, an individual needed to exhibit “a pervasive lack of responsiveness to other people” [emphasis added].

Introduced from 1994, the DSM-IV had broader criteria, and folded Asperger disorder into ASD. With the introduction of the DSM-V, new diagnoses were curbed – for a time. This is because about 20% of the children diagnosed with ASD under DSM-IV-TR would not have received one under the DSM-V. The DSM-V relaxed the criteria for language delay, co-occurrence, and IQ, making it easier for borderline cases to qualify for a diagnosis.

Another underappreciated element is that of social contagion. If parents know a family with a child with ASD, they may be more likely to seek a diagnosis. One study from California showed that ASD diagnoses were more likely the more other ASD diagnoses under one kilometre away.

Back to square one

Considering the weakness of the cited studies, the difficulty of explaining ASD, the underlying social phenomenon of shifting diagnostic thresholds and increased awareness, it seems as though these announcements are mostly without substance. In amidst the headline-grabbing news, the NIH quietly announced the launch of a $50 million initiative into the causes of ASD.

According to the news release, the NIH will fund 13 projects “that draw on genomic, epigenomic, metabolomic, proteomic, clinical, behavioral and autism services data. These projects will integrate, aggregate and analyze existing data resources, generate targeted new data and validate findings through independent replication hubs.”

With this in mind, it really doesn’t look like paracetamol is the singular, mysterious controllable risk factor for ASD rates that President Trump and Robert F. Kennedy Jr have made it out to be. Maybe paracetamol use simply reflects infection, or some other related factor.

Categories : Medical Research & Technology Respiratory DiseasesTags :

No Benefits Seen from Conservative Oxygen in the ICU

On By ModernMedia
Photo by engin akyurt on Unsplash

A UK trial involving 16 500 mechanically ventilated intensive care unit (ICU) patients found no 90-day survival benefit for conservative supplemental oxygen over usual oxygen therapy. Nevertheless, the study, published in JAMA, did demonstrate the accuracy and cost-effectiveness of conducting a large trial with a simple intervention.

Oxygen is one of the most commonly administered treatments to patients in ICUs, but liberal oxygen therapy to avoid the risks of hypoxaemia may lead to harm, so finding the right level could optimise outcomes. Trials to date have shown mixed results.

For COVID patients admitted to the ICU with severe hypoxaemia, survival without life support was extended with conservative oxygen therapy. In a paediatric ICU study, conservative oxygen therapy resulted in a reduction in a composite of organ support at 30 days or death. A meta-analysis of 13 trials showed no differences between liberal and conservative oxygen therapy.

Even with just a small difference in survival benefit, with tens of millions of patients mechanically ventilated in the ICU would still mean significant numbers of lives saved. Other tests of new drugs and procedures in the ICU are hampered by high cost, as Seitz et al. noted in an accompanying editorial, so this sort of trial comparing two approaches to a common therapy is much more affordable.

The UK Intensive Care Unit Randomised Trial Comparing Two Approaches to Oxygen Therapy (UK-ROX) trial was initiated to determine if there was a difference between conservative and usual oxygen therapy.

The trial randomised 16 500 patients across 97 ICUs in the UK to either conservative oxygen therapy or usual oxygen therapy, in adults receiving mechanical ventilation and supplemental oxygen in the ICU. The primary outcome was mortality at 90 days. Conservative oxygen therapy targeted a peripheral oxygen saturation (Spo2) of 90% (range, 88%-92%), while usual oxygen therapy was at the discretion of the treating clinician.

Patients were early in mechanical ventilation (median, 5 hours), were severely ill (median predicted mortality risk, 35%), had a range of critical illnesses (eg, > 5000 patients with sepsis and > 1500 patients with hypoxic-ischaemic encephalopathy) and with significant hypoxaemia (eg, > 11 000 patients with a Pao2:Fio2 ratio, consistent with acute respiratory distress syndrome). Obtaining informed consent from the patients was, of course, largely not feasible, so this requirement was waived for the study.

Exposure to supplemental oxygen was 29% lower for those in the conservative oxygen therapy group compared with the usual oxygen therapy group. Of the patients randomised to conservative oxygen therapy, 35.4% died by 90 days compared with 34.9% of patients receiving usual oxygen therapy.

No differences were seen for secondary outcomes, including ICU stay, days free of life support and mortality at various time points. No interactions for confirmed or suspected COVID, ethnicity or other illnesses were observed.

Post hoc analysis showed weak evidence of increased harm from conservative oxygen therapy among the first 10 patients in each site but no difference for the random enhanced data collection sample compared with standard data collection.

Seitz et al. pointed out that the high level of adherence to the conservative target resulted in a mean oxygen saturation of 93.3%, versus 95.1% for usual care. The differences in oxygen saturation (1.9%) and Fio2 (0.04) between the trial groups in UK-ROX were about half the magnitude of some prior trials, due to not aiming for widely separated targets, and usual care varies considerably depending on location and clinical considerations.

Therefore, the researchers concluded that the findings do not support an approach of reducing oxygen exposure by targeting an Spo2 of 90% in mechanically ventilated adults receiving oxygen in the ICU. They suggest that future research may involve using AI to determine specific situations where conservative or liberal oxygen therapy may have beneficial outcomes.

References:

Martin DS, Gould DW, Shahid T, et al. Conservative Oxygen Therapy in Mechanically Ventilated Critically Ill Adult Patients: The UK-ROX Randomized Clinical Trial. JAMA. 2025;334(5):398–408. doi:10.1001/jama.2025.9663

Seitz KP, Casey JD, Semler MW. Patient, Treatment, Outcome—Large Simple Trials of Common Therapies. JAMA. 2025;334(5):395–397. doi:10.1001/jama.2025.9657

Categories : Cancer Neurodegenerative DiseasesTags :

Breast Cancer Treatment Linked to a Reduction in Alzheimer’s Disease Risk

On By ModernMedia
Photo by National Cancer Institute on Unsplash

A Korean population-based cohort study investigated the risk of Alzheimer’s disease (AD) among breast cancer survivors compared to age-matched controls without cancer. The study, published in JAMA Network Open, found that breast cancer survivors had an 8% lower risk of AD than controls, with a significant association in survivors over 65 years old – though the effect did not persist past five years. Radiotherapy was associated with a lower risk of AD among breast cancer survivors – but not other treatments.

Breast cancer survivors may experience long-term health consequences, including cognitive function and risk of dementia. The risk of AD among breast cancer survivors is still unclear and may vary depending on age at diagnosis, treatment received, and time since treatment.

Previous studies reported mixed results on the risk of AD among breast cancer survivors, with some finding no increase in risk and others finding a 35% increased risk for those diagnosed at age 65 or older. These studies have been hampered by a number of methodological issues, including not accounting for risk factors.

Cytotoxic chemotherapy can cause cognitive decline termed ‘chemobrain’. Other chemotherapy drugs such as anthracycline may reduced AD risk by reducing the formation of amyloid deposits. Endocrine therapy may increase the risk of dementia by lowering oestrogen, but studies suggest that the use of tamoxifen and aromatase inhibitors is associated with a lower risk of AD. An increase in dementia is seen in radiotherapy for head and neck cancers.

To investigate the risk of AD among breast cancer survivors, researchers used the Korean National Health Insurance Service (K-NHIS) database, exploring whether there is an association with cancer treatment and various confounding factors.

Among 70 701 breast cancer survivors (mean age, 53.1 years), 1229 cases of AD were detected, with an incidence rate of 2.45 per 1000 person-years. Survivors exhibited a slightly lower risk of AD compared with cancer-free controls, especially among individuals 65 years or older (SHR, 0.92; 95% CI, 0.85-0.99). But landmark analyses found that this lower risk did not persist beyond five years of survival. Radiotherapy was associated with reduced risk of AD among survivors, while chemotherapy and endocrine therapy had no significant impact. Anthracycline use, however, did show a non-significant decrease in risk.

Differences in doses and timing of radiotherapy may influence the effects. The incident exposure to the brain is estimated to be 0.2Gy from a breast cancer radiotherapy dose of 50Gy. A pilot study found that patients with AD who received low-dose whole-brain radiotherapy at 3Gy showed a temporary improvement in cognitive function. This improvement is believed to be due to a neuroprotective effect on microglia. Other studies have noted a transient risk reduction for AD in breast cancer radiotherapy; however, patients receiving radiotherapy usually do so in conjunction with breast-conserving surgery – those opting for this procedure are younger, with fewer comorbidities and smaller tumours.

The study suggests that cancer treatment may have benefits against AD development, but the risk of AD may differ depending on the duration of survival.

The findings indicate that breast cancer treatment may not directly lead to AD, and that managing modifiable risk factors for AD, such as smoking and diabetes, is a feasible option to lower AD risk among breast cancer survivors.

Categories : VaccinesTags :

Amid Surge in Cases, UK’s NHS to Offer Gonorrhoea Vaccine

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Neisseria gonorrhoeae Bacteria Scanning electron micrograph of Neisseria gonorrhoeae bacteria, which causes gonorrhoea. Captured by the Research Technologies Branch (RTB) at the NIAID Rocky Mountain Laboratories (RML) in Hamilton, Montana. Credit: NIAID. Photo by National Institute of Allergy and Infectious Diseases on Unsplash

In the midst of a record high in gonorrhoea cases, the NHS is to offer a gonorrhoea vaccine to gay and bisexual men with a history of multiple partners or a sexually transmitted infection (STI), the BBC reports. The gonorrhoea vaccination, which is actually a repurposed meningococcal vaccine, is estimated only to be 30–40% effective. Research shows, however, that this will be sufficient to reduce cases and their attendant costs to the NHS.

Gonorrhoea is caused by the bacterium Neisseria gonorrhoeae and is typically transmitted by having intercourse without a condom. It can cause pain, unusual discharge, genital inflammation and infertility. Evidence has shown that the MeNZB and four-component serogroup B meningococcal (4CMenB) vaccines, designed against Neisseria meningitidis, can also offer protection against gonorrhoea.

In 2023, there were more than 85 000 cases – the highest since records began in 1918. A study published in The Lancet estimates that gonorrhoea vaccination would prevent 100 000 cases, saving the NHS £7.9 million over the next decade.

While gonorrhoea is treatable with antibiotics, resistance is growing and there is concern that it may eventually become untreatable. According to The Guardian, some cases are now “extensively drug resistant” (XDR) – not responsive to ceftriaxone or the second line of treatment. There were 17 cases of ceftriaxone-resistant gonorrhoea between January 2024 and March 2025, the UK Health Security Agency (UKHSA) reported.

Over the same period, nine XDR cases were reported, while between 2022 and 2023, there were only five.

The people most affected by gonorrhoea in the UK are the 16 to 25 age group, gay and bisexual men, and those of black and Caribbean ancestry. The study’s scenario for vaccinating at-risk populations included those who had more than five sexual partners per year or who had a positive gonorrhoea test.

The vaccine, costing about £8 per dose, is cost-effective when administered to this at-risk group of men, rather than adolescents. Despite this, clinicians will be able to offer the vaccine to anyone who, in their judgment, would benefit from it. Other vaccines such as for mpox – another STI with high transmission between gay and bisexual men – and hepatitis will also be offered.

Categories : Ethics and Law UrogenitalTags :

Court Rules that UTI Drug Trade Names are Too Similar

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A court case over the trade names of two urinary tract infection (UTI) drugs has been settled. The court ordered that Cipla Medpro be restrained from using the trade name Furizome as it is too similar to Adcock Ingram’s UTI drug Urizone, leading to potential confusion by consumers. In his ruling, Justice James Lekhuleni of the High Court, Western Cape Division, who stated that despite safeguards against confusion in prescribing, ultimately “doctors are human”, so miscommunications could occur – and that the agency of patients cannot be ignored.

The trademark infringement case was brought by three applicants: Adcock Ingram Limited, Adcock Ingram Healthcare (Pty) LTD, and Italian company Zambon S.P.A. Zambon is the owner of the name Urizone, which is used under licence. Urizone had been launched in South Africa in 1993. The applicants stated that more than 3 million sachets had been sold between 2011 and 2023, with R5 million in advertising spent to promote the drug between 2018 and 2022 alone.

The applicants brought the case that Cipla Medpro’s Furizome, with the active ingredient fosfomycin, was too similar to their own product, Urizone, which contained the same ingredient in 3g sachets, and thus could confuse consumers. They alleged that Cipla Medpro sought to capitalise on the reputation earned by Urizone.

The applicants made the case that, despite Urizone being made available as a generic, none of the pharmaceutical companies producing it chose to use the name. When Furizome was launched, Adcock Ingram sent a letter of demand to Cipla to stop using the name due to its . Cipla, through its attorneys, rebutted the claim, saying that the two are sufficiently distinct to avoid confusion, with the “F” alluding to the fosfomycin ingredient. Cipla contended that it had already submitted the name through SAHPRA, and

Cipla also contended that the consumer – the patient – would not be misled during the prescribing and purchase of a schedule 4 medication as they would be informed by the pharmacist of the two different drugs.

In considering the judgment, the court noted that a test as to whether trademarks are be similar can be mode on a phonetic basis, or if they conceptually or visually similar. A trademark’s essential function is to indicate the origin of the goods in connection with which it is used. The “N” and “M” where seen as visually and phonetically similar, and “furi” was similar phonetically to “uri“. This could cause confusion and miscommunication even between doctors as to what drug they had prescribed a patient.

While Justice Lekhuleni acknowledged the safeguards of prescribing schedule 4 medications, he pointed out that the general public had become much more knowledgeable about prescription drugs in the past two decades. On this, he wrote “…the reality is that patients are involved in the process of deciding which medicines they will use, and that creates the risk of confusion. This situation in turn creates a responsibility upon pharmaceutical companies to make sure that they adopt trade marks that are not confusingly similar.”

Categories : NeurologyTags :

Leakiness of First Blood–brain Barrier Layer Results in Cognitive Deficits

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a, Diagram of the BBB and brain endothelial glycocalyx layer. b, TEM of cortical capillaries with lanthanum nitrate staining from young (3-month-old) and aged (21-month-old) mice. Scale bars, 1 µm. Source: Shi et al., Nature, 2025.

A study published in Nature reveals how a key component of the blood–brain barrier (BBB), the endothelial glycocalyx layer, becomes dysregulated in ageing, causing the BBB to become compromised. The researchers also investigated the possibility of to restore this layer’s integrity, reducing neuroinflammation and restoring cognitive function.

The BBB is a highly specialised safeguard keeping the brain separate from harmful factors, such as toxins and also albumin, IgG and fibrinogen (and, unfortunately, many medications which could otherwise treat brain disease). The leakage of such blood-derived molecules into the brain has been shown to trigger neuroinflammatory changes and create a neurotoxic brain environment. The part of the BBB directly in contact with the blood is the endothelial glycocalyx layer, a carbohydrate-rich meshwork mostly composed of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen. Yet the endothelial glycocalyx’s composition and role is poorly understood despite it being the first layer of interface between the blood and brain.

The researchers found that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. Two mucin-type O-glycan biosynthetic enzymes, C1GALT1 and B3GNT3 were also found to be downregulated mouse models of ageing and in the brains of Alzheimer’s and Huntington’s disease patients. To test these, the researchers used adeno-associated viruses (AAV) in young mice to turn down the expression of C1GALT1 and B3GNT3. These mice showed signs of BBB leakage and in severe cases, brain haemorrhaging occurred in mice.

In samples from the brains of Alzheimer’s patients, the researchers also observed reduced C1GALT1 in microvessels.

To test if it was possible to restore the BBB’s ability to protect the brain against harmful blood-borne molecules, they administered AAVs in aged mice to restore levels of B3GNT3 and C1GALT1.

Assessing cognitive function, they found that aged mice treated with B3GNT3 via an AAV displayed improvements in spatial working memory in a maze test and hippocampal-dependent learning and memory in a fear conditioning test. Aged mice treated with C1GALT1 did not improve in the maze test, and no significant difference was observed in cued freezing in the fear conditioning among the three aged groups.

Although the study shows that increasing C1GALT1 and B3GNT3 reduces BBB permeability and improves brain health, the precise mechanisms that underlie these beneficial effects remain unclear. The researchers believe that by limiting the nonspecific uptake of blood-derived molecules, the brain can be protected. But C1GALT1 and B3GNT3 are also likely to influence a wide range of proteins and glycan structures and in order to further understand brain ageing and rejuvenation it is therefore crucial to understand the molecular pathways affected by them.

The authors concluded: “Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.”

Categories : Healthcare Politics and RegulationsTags :

Healthcare Organisations React to US Withdrawal from the WHO

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One of the first acts President Trump took on assuming office again on January 20, 2025, was to unilaterally withdraw the United States from the World Health Organization (WHO). Trump complained of the WHO’s “mishandling” of the COVID pandemic, influence by other countries, and the US financial support was excessive compared to China, which “has 300 percent of the population of the United States, yet contributes nearly 90 percent less to the WHO.”

The WHO released a statement, expressing its regret at the decision and pointing out its importance: “WHO plays a crucial role in protecting the health and security of the world’s people, including Americans, by addressing the root causes of disease, building stronger health systems, and detecting, preventing and responding to health emergencies, including disease outbreaks, often in dangerous places where others cannot go.”

The organisation also took aim at Trump’s criticism of its lack of reforms: “With the participation of the United States and other Member States, WHO has over the past 7 years implemented the largest set of reforms in its history, to transform our accountability, cost-effectiveness, and impact in countries. This work continues.”

Critics say that the move would only hand China the opportunity to effectively take control of global health if it chooses to becomes the WHO’s main contributor: though the US is the single largest contributor, it contributed only $1.3 billion in the 2022-23 biennium. An affordable amount compared to the vast sums both countries spend on their militaries. While the WHO did lavish praise on China, many experts saw it as undue and perhaps concerning – but China’s contribution, while currently small, is rising: $86 million in the 2018-19 biennium. After the US, the next largest contributors are Germany ($856 million) and the Bill and Melinda Gates Foundation ($830 million).

The Society for Healthcare Epidemiology of America (SHEA) stressed the importance of global health cooperation. In a statement, the organisation wrote: “It is essential that the United States continues our connection with the WHO to coordinate surveillance, monitoring, detection, prevention, research, and response to public health threats including outbreaks, antimicrobial resistance and high consequence pathogens such as viral haemorrhagic fevers (Ebola, Marburg), Mpox, and highly pathogenic avian influenza (eg, H5N1).”

Indeed, Trump may not simply be able to withdraw by presidential decree; since the US joined the WHO by an act of Congress, it would likely take congressional approval to leave it and Trump may face a lawsuit over this.

Trump previously announced his intention to withdraw the US from the WHO in 2020, something which Gostin et al. warned in The Lancet would not work out well for the US and the world. “Withdrawal from WHO would have dire consequences for US security, diplomacy, and influence. WHO has unmatched global reach and legitimacy.” Additionally, they warned of the sheer difficulty of such a messy divorce: “The US administration would be hard pressed to disentangle the country from WHO governance and programmes.”

Categories : Cardiovascular Disease New Compounds and TreatmentsTags :

Deep Depletion of Blood Lipoprotein(a) Levels with New Drug

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Image by Scientific Animations, CC4.0

In a new study, researchers found that a new drug under development, zerlasiran, depleted levels of lipoprotein(a) by more than 80% in participants with increased cardiovascular risk. The drug was well tolerated and the findings, published in JAMA Network, suggest that this could be the first viable treatment for elevated levels of lipoprotein(a).

Elevated levels of lipoprotein(a) (LPa) – a type of cholesterol – is a genetic risk factor for cardiovascular disease. Present in 20% of the population, it increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Currently, there are no interventions which can bring down high LPa levels: it is unresponsive to diet, exercise, and other lifestyle changes and there is no available drug.

Zerlasiran, a small-interfering RNA that targets synthesis of LPa serum concentration, was developed to fill this gap. It is effectively a gene silencer that shuts down LPA, a gene which produces a protein found only in LPa. This in turn is expected to reduce cardiovascular risk.

A phase I clinical trial had shown that zerlasiran was safe and effective.

For the study, researchers enrolled 178 patients (average age 63.7 years, 46 female) with ASCVD and LPa concentrations greater than or equal to 125nmol/L. They were randomised to subcutaneously receive zerlasiran 300mg or 450mg, or a placebo, every 16 or every 24 weeks. The least-squares mean placebo-adjusted time-averaged percent change in LPa serum concentrations was −85.6%, −82.8%, and −81.3% for the 450mg every 24 weeks, 300mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. The most common adverse events were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug. For the group receiving a 300mcg dose every 16 weeks, it was found that even at the 60 week follow-up, 28 weeks after the last administration, that lipoprotein(a) serum concentrations were still 60% lower than baseline.